This invention is directed at enhancing vascular function in patients with vascular diseases and conditions that are associated with deficient nitric oxide bioactivity, endothelial dysfunction, tetrahydrobiopterin insufficiency and/or oxidative stress. In an embodiment the oxidative stress triggers the tetrahydrobiopterin insufficiency which in turn triggers deficient nitric oxide bioactivity and endothelial dysfunction, and the invention is directed at treating the vascular diseases and conditions associated with the endothelial dysfunction.
It is known that nitric oxide is constitutively produced by vascular endothelial cells where it plays a key physiological role in the moment-to-moment regulation of blood pressure and vascular tone.
It is known that deficient nitric oxide bioactivity contributes to the pathogenesis of vascular dysfunctions, including coronary artery disease, atherosclerosis, hypertension, diabetic vasculapathy and neurodegenerative conditions stemming from ischemia and/or inflammation, and that such pathogenesis includes damaged endothelium, poor flow of oxygenated blood resulting in oxygen-deficient organs and tissues, elevated systemic vascular resistance (high blood pressure), vascular smooth muscle proliferation, progression of vascular stenosis and inflammation.
There is no current medically established solution for reversing or diminishing the deficiency in nitric oxide bioactivity. However, health food stores sell arginine and arginine-containing preparations as dietary supplements, and efficacy in reversing conditions associated with endothelial dysfunction has been suggested. Administration of tetrahydrobiopterin has also been suggested to increase nitric oxide bioactivity by blood vessels of chronic smokers and in animal models of atherosclerosis.
It has been discovered in the course of making the invention that a predominant reason for nitric oxide (NO) deficiency in disorders involving endothelial dysfunction associated with deficient nitric oxide bioactivity is that dihydrobiopterin (BH2) binds to eNOS (an enzyme associated with constitutive nitric oxide production in endothelial cells of blood vessels) with affinity equal to the natural cofactor tetrahydrobiopterin (BH4), but that whereas BH4-bound eNOS mediates production of nitric oxide, BH2-bound eNOS does not. Rather BH2-bound eNOS causes diminished nitric oxide to be present by producing superoxide anion that reacts with nitric oxide to inactivate it. BH2-bound eNOS also causes a cascade effect by producing superoxide anion which oxidizes BH4 to BH2 and still greater rate of superoxide production and further diminished production of nitric oxide and increased inactivation of nitric oxide. Oxidative conditions that can predominate in vascular disorders can oxidize BH4 to BH2, thereby initiating this cascade. It is also discovered in the course of making the invention herein that hydroxyarginine, and other hydroxyguanidine-containing molecules can be metabolized to nitric oxide by BH2-bound eNOS.
The invention herein is directed to a method of treating a patient with a disorder involving endothelial dysfunction associated with deficient nitric oxide bioactivity by restoring or increasing nitric oxide bioactivity in the patient and comprises administering to the patient a therapeutically effective amount of nitric oxide bioactivity increasing agent selected from the group consisting of nitric oxide bioactivity increasing hydroxyguanidines and pharmaceutically acceptable salts thereof, optionally in combination with arginine and/or tetrahydrobiopterin, thereby increasing or restoring nitric oxide bioactivity.
The endothelial dysfunction referred to is diagnosed by the failure of intracoronary infusion of 1 xcexcmol/liter of acetylcholine in physiological saline to elicit an increase in coronary artery luminal diameter in a patient undergoing coronary angiography. An alternative non-invasive approach to assess endothelial dysfunction may be performed by measurement of flow-mediated vasodilation of the brachial artery using an ultrasound-based imaging technique. For this test, forearm brachial artely diameter is determined by ultrasound in the patient prior to testing. Subsequently, a pneumatic tourniquet is placed below the patient""s elbow, inflated to 300 mm Hg and held at this pressure for 5 minutes. The tourniquet is then rapidly released and the flow-induced increase in luminal diameter is recorded at 1 min after release. If the observed flow-induced increase in luminal diameter averages 5% or less with 4 repeat measurements, a diagnosis of endothelial dysfunction is made.
The deficiency in nitric oxide bioactivity referred to above is due to oxidative stress which oxidizes some of the normally present nitric oxide and/or oxidizes tetrahydrobiopterin cofactor for nitric oxide production making it inactive, so as to deplete nitric oxide bioactivity.